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ATM Mutations in Patients with Hereditary Pancreatic Cancer
Open accessPublished version of a preprint
Abstract
Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41–6. ©2011 AACR. Read the Commentary on this article by Bakker and de Winter, p. 14 This article is highlighted in the In This Issue feature, p. 1
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“Pancreatic surveillance is recommended for carriers of germline deleterious variants in cancer susceptibility gene,22–26: BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.”
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Metadata
- Authors
- Roberts, N. J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G. M., Bondy, M. L., Gallinger, S., Schwartz, A. G., Syngal, S., Cote, M. L., Axilbund, J., Schulick, R., Ali, S. Z., Eshleman, J. R., Velculescu, V. E., Goggins, M., Vogelstein, B., Papadopoulos, N., Hruban, R. H., Kinzler, K. W., & Klein, A. P.
- Affiliations
- Brigham and Women's Hospital (US)
- Authors' Affiliations: 1Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center; Departments of 2Medicine, 3Pathology, 4Surgery, and 5Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions; 6Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland; 7Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; 8Division of Epidemiology, Mayo Clinic, Rochester, Minnesota; 9Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; 10Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; 11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; 12Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts
- Mayo Clinic (US)
- Corresponding author
- Hruban, Ralph H.
- Kinzler, Kenneth W.
- Klein, Alison P.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2012-01-01
- Volume
- 2
- Issue
- 1
- Pages
- 41-46
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3676748
- OpenAlex
- W2146542392
- Cited by
- 491
- References
- 30
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 22 · 2023: 27 · 2022: 30 · 2021: 49 · 2020: 36 · 2019: 43 · 2018: 42 · 2017: 38 · 2016: 49 · 2015: 41 · 2014: 38 · 2013: 31 · 2012: 20
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01pc35145-19-0-7, n01cn43302-6-0-1, 5r01ca121113-15)
- National Cancer Institute (N01 CN043302, R01CA-97075, CA123483, R01CA123483, R01-CA121113, N01 PC035145, CA-121113, N01 PC 35145, CA057345, P50CA102701, R01CA057345, R01CA097075, N01-CN 43302, P50CA062924, R37CA057345, CA 62924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- ATM gene, hereditary pancreatic cancer, pancreatic ductal adenocarcinoma, hereditary cancer predisposition, loss of heterozygosity, constitutional mutation, cancer susceptibility genes, hereditary cancer
- MeSH terms
- Ataxia Telangiectasia, DNA-Binding Proteins, Humans, Mutation, Pancreatic Neoplasms, Pedigree, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Tumor Suppressor Proteins, Genome-Wide Association Study, Exome, Ataxia Telangiectasia Mutated Proteins
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